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Dose-response met-RANTES treatment of experimental periodontitis: a narrow edge between the disease severity attenuation and infection control.

Repeke CE, Ferreira SB, Vieira AE, Silveira EM, Avila-Campos MJ, da Silva JS, Santos CF, Campanelli AP, Trombone AP, Garlet GP - PLoS ONE (2011)

Bottom Line: At 0.5 mg up to 5 mg doses, a strong reduction in the alveolar bone loss and inflammatory cell migration were observed.Interestingly, 5 mg dose treatment resulted in the maximum inhibition of inflammatory cell migration, but resulted in a similar inhibition of bone loss when compared with the lower doses, and also resulted in increased bacterial load and CRP response.When 0.5 and 5 mg therapy regimens were compared it was observed that both therapeutic protocols were able to downregulate the levels of pro-inflammatory, Th1-type and osteoclastogenic cytokines, and CD3+ and F4/80+ cells migration to periodontal tissues, but the high dose modulates host response in a more pronounced and unspecific and excessive way, interfering also with the production of antimicrobial mediators such as MPO, iNOS and IgG, and with GR1+ and CD19+ cells migration.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, School of Dentistry of Bauru, São Paulo University-FOB/USP, Bauru, Sao Paulo, Brazil.

ABSTRACT
Chemokines and chemokine receptors have been implicated in the selective migration of leukocyte subsets to periodontal tissues, which consequently influences the disease outcome. Among these chemoattractants, the chemokines CCL3, CCL4 and CCL5 and its receptors, CCR1 and CCR5, have been associated with increased disease severity in mice and humans. Therefore, in this study we investigated the modulation of experimental periodontitis outcome by the treatment with a specific antagonist of CCR1 and 5 receptors, called met-RANTES. C57Bl/6 mice was orally infected with Aggregatibacter actinomycetemcomitans and treated with 0.05, 0.1, 0.5, 1.5 and 5 mg doses of met-RANTES on alternate days, and evaluated by morphometric, cellular, enzymatic and molecular methods. At 0.5 mg up to 5 mg doses, a strong reduction in the alveolar bone loss and inflammatory cell migration were observed. Interestingly, 5 mg dose treatment resulted in the maximum inhibition of inflammatory cell migration, but resulted in a similar inhibition of bone loss when compared with the lower doses, and also resulted in increased bacterial load and CRP response. When 0.5 and 5 mg therapy regimens were compared it was observed that both therapeutic protocols were able to downregulate the levels of pro-inflammatory, Th1-type and osteoclastogenic cytokines, and CD3+ and F4/80+ cells migration to periodontal tissues, but the high dose modulates host response in a more pronounced and unspecific and excessive way, interfering also with the production of antimicrobial mediators such as MPO, iNOS and IgG, and with GR1+ and CD19+ cells migration. Our results demonstrate a thin line between beneficial immunoregulation and impaired host defense during experimental periodontitis, and the determination of the exact equilibrium point is mandatory for the improvement of immune-targeted therapy of periodontitis.

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Met-RANTES treatment at different doses modulate Th1, Th2, Th17 cytokine and osteclastogenic factor RANKL levels in experimental periodontitis.C57Bl/6 mice were infected orally with AA, treated with met-RANTES at 0.5 and 5 mg doses or (V) veicule, (-) non treated and (C) control non-infected mice, sacrificed at day 30 post-infection and evaluated for levels of A) IFN-γ, a Th1 cytokine; B) IL-4, a Th2 cytokine; C) IL-17A, a Th17 cytokine and D) the major osteoclastogenic factor RANKL. Different italic low case letters represent statistically significant differences among the doses in the same experimental group (P<0.05; One-way ANOVA).
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pone-0022526-g004: Met-RANTES treatment at different doses modulate Th1, Th2, Th17 cytokine and osteclastogenic factor RANKL levels in experimental periodontitis.C57Bl/6 mice were infected orally with AA, treated with met-RANTES at 0.5 and 5 mg doses or (V) veicule, (-) non treated and (C) control non-infected mice, sacrificed at day 30 post-infection and evaluated for levels of A) IFN-γ, a Th1 cytokine; B) IL-4, a Th2 cytokine; C) IL-17A, a Th17 cytokine and D) the major osteoclastogenic factor RANKL. Different italic low case letters represent statistically significant differences among the doses in the same experimental group (P<0.05; One-way ANOVA).

Mentions: In order to determine the mechanisms underlying the differential response to 0.5 and 5 mg met-RANTES doses, we next analyzed the levels of several cytokines in periodontal tissues of mice by ELISA (Fig. 3). Our results demonstrate that, as a general rule, both 0.5 and 5 mg were able to decrease the production of proinflammatory cytokines IL-1β, TNF-α and IL-6 in periodontal tissues, but in different degrees, since 5 mg dose resulted in a higher decrease of TNF-α and IL-6 when compared to the 0.5 mg dose. Complementarily, our data demonstrate that only the 5 mg dose resulted in a significant modulation of the anti-inflammatory cytokine IL-10 when compared to the other experimental groups. When T helper-signature cytokines were evaluated (Fig. 4), it was observed that IFN-γ levels were significantly reduced by both 0.5 and 5 mg when compared to controls, but this change was significantly more prominent with the 5 mg dose. Regarding IL-4 and IL-17A levels, only the 5 mg dose resulted in a decrease in the level of such cytokines in the periodontal tissues of AA-infected mice. Finally, we observed that both 0.5 and 5 mg treatment resulted in decreased levels of RANKL in periodontal tissues at the same extent, when compared to the controls.


Dose-response met-RANTES treatment of experimental periodontitis: a narrow edge between the disease severity attenuation and infection control.

Repeke CE, Ferreira SB, Vieira AE, Silveira EM, Avila-Campos MJ, da Silva JS, Santos CF, Campanelli AP, Trombone AP, Garlet GP - PLoS ONE (2011)

Met-RANTES treatment at different doses modulate Th1, Th2, Th17 cytokine and osteclastogenic factor RANKL levels in experimental periodontitis.C57Bl/6 mice were infected orally with AA, treated with met-RANTES at 0.5 and 5 mg doses or (V) veicule, (-) non treated and (C) control non-infected mice, sacrificed at day 30 post-infection and evaluated for levels of A) IFN-γ, a Th1 cytokine; B) IL-4, a Th2 cytokine; C) IL-17A, a Th17 cytokine and D) the major osteoclastogenic factor RANKL. Different italic low case letters represent statistically significant differences among the doses in the same experimental group (P<0.05; One-way ANOVA).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140528&req=5

pone-0022526-g004: Met-RANTES treatment at different doses modulate Th1, Th2, Th17 cytokine and osteclastogenic factor RANKL levels in experimental periodontitis.C57Bl/6 mice were infected orally with AA, treated with met-RANTES at 0.5 and 5 mg doses or (V) veicule, (-) non treated and (C) control non-infected mice, sacrificed at day 30 post-infection and evaluated for levels of A) IFN-γ, a Th1 cytokine; B) IL-4, a Th2 cytokine; C) IL-17A, a Th17 cytokine and D) the major osteoclastogenic factor RANKL. Different italic low case letters represent statistically significant differences among the doses in the same experimental group (P<0.05; One-way ANOVA).
Mentions: In order to determine the mechanisms underlying the differential response to 0.5 and 5 mg met-RANTES doses, we next analyzed the levels of several cytokines in periodontal tissues of mice by ELISA (Fig. 3). Our results demonstrate that, as a general rule, both 0.5 and 5 mg were able to decrease the production of proinflammatory cytokines IL-1β, TNF-α and IL-6 in periodontal tissues, but in different degrees, since 5 mg dose resulted in a higher decrease of TNF-α and IL-6 when compared to the 0.5 mg dose. Complementarily, our data demonstrate that only the 5 mg dose resulted in a significant modulation of the anti-inflammatory cytokine IL-10 when compared to the other experimental groups. When T helper-signature cytokines were evaluated (Fig. 4), it was observed that IFN-γ levels were significantly reduced by both 0.5 and 5 mg when compared to controls, but this change was significantly more prominent with the 5 mg dose. Regarding IL-4 and IL-17A levels, only the 5 mg dose resulted in a decrease in the level of such cytokines in the periodontal tissues of AA-infected mice. Finally, we observed that both 0.5 and 5 mg treatment resulted in decreased levels of RANKL in periodontal tissues at the same extent, when compared to the controls.

Bottom Line: At 0.5 mg up to 5 mg doses, a strong reduction in the alveolar bone loss and inflammatory cell migration were observed.Interestingly, 5 mg dose treatment resulted in the maximum inhibition of inflammatory cell migration, but resulted in a similar inhibition of bone loss when compared with the lower doses, and also resulted in increased bacterial load and CRP response.When 0.5 and 5 mg therapy regimens were compared it was observed that both therapeutic protocols were able to downregulate the levels of pro-inflammatory, Th1-type and osteoclastogenic cytokines, and CD3+ and F4/80+ cells migration to periodontal tissues, but the high dose modulates host response in a more pronounced and unspecific and excessive way, interfering also with the production of antimicrobial mediators such as MPO, iNOS and IgG, and with GR1+ and CD19+ cells migration.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, School of Dentistry of Bauru, São Paulo University-FOB/USP, Bauru, Sao Paulo, Brazil.

ABSTRACT
Chemokines and chemokine receptors have been implicated in the selective migration of leukocyte subsets to periodontal tissues, which consequently influences the disease outcome. Among these chemoattractants, the chemokines CCL3, CCL4 and CCL5 and its receptors, CCR1 and CCR5, have been associated with increased disease severity in mice and humans. Therefore, in this study we investigated the modulation of experimental periodontitis outcome by the treatment with a specific antagonist of CCR1 and 5 receptors, called met-RANTES. C57Bl/6 mice was orally infected with Aggregatibacter actinomycetemcomitans and treated with 0.05, 0.1, 0.5, 1.5 and 5 mg doses of met-RANTES on alternate days, and evaluated by morphometric, cellular, enzymatic and molecular methods. At 0.5 mg up to 5 mg doses, a strong reduction in the alveolar bone loss and inflammatory cell migration were observed. Interestingly, 5 mg dose treatment resulted in the maximum inhibition of inflammatory cell migration, but resulted in a similar inhibition of bone loss when compared with the lower doses, and also resulted in increased bacterial load and CRP response. When 0.5 and 5 mg therapy regimens were compared it was observed that both therapeutic protocols were able to downregulate the levels of pro-inflammatory, Th1-type and osteoclastogenic cytokines, and CD3+ and F4/80+ cells migration to periodontal tissues, but the high dose modulates host response in a more pronounced and unspecific and excessive way, interfering also with the production of antimicrobial mediators such as MPO, iNOS and IgG, and with GR1+ and CD19+ cells migration. Our results demonstrate a thin line between beneficial immunoregulation and impaired host defense during experimental periodontitis, and the determination of the exact equilibrium point is mandatory for the improvement of immune-targeted therapy of periodontitis.

Show MeSH
Related in: MedlinePlus